“Pembrolizumab plus pemetrexed and platinum may be a new standard of care for first-line treatment of metastatic non-squamous NSCLC, irrespective of PD-L1 expression.”

~Leena Gandhi, MD

The double-blind, randomised-controlled, Phase III KEYNOTE-189 study recruited 616 treatment-naïve advanced and metastatic non-squamous NSCLC patients to receive frontline pembrolizumab or placebo (2:1) in combination with pemetrexed and investigator-choice cisplatin or carboplatin. Patients could enrol regardless of PD-L1 expression status but were required to be EGFR– and ALK-negative.

All patients received induction chemotherapy of pemetrexed 500 mg/m2 plus either cisplatin 75 mg/m2 or carboplatin (AUC 5) on day 1 every 3 weeks for 4 cycles plus pembrolizumab at a fixed dose of 200 mg every 3 weeks or matching placebo. Maintenance pemetrexed was offered to all patients at 500 mg/m2 every 3 weeks. Additionally, patients received 200 mg of pembrolizumab or matching placebo.

Overall Survival

At the time of data cut-off in November 2017, the median follow-up was 10.5 months. In the pembrolizumab-arm, the estimated 12-month OS rate was 69.2% (95% confidence interval [CI], 64.1-73.8) compared to 49.4% (95% CI, 42.1-56.2) in the placebo group (hazard ratio [HR]=0.49, P<0.001; 95% CI, 0.38-0.64).

The median OS was not reached in patients receiving pembrolizumab plus chemotherapy. In the group receiving placebo plus chemotherapy, the median OS was 11.3 months (95% CI, 8.7-15.1) in the chemotherapy-alone arm. The observed OS benefit was irrespective of PD-L1 expression status.

Figure 1. Kaplan-Meier estimate for OS in the KEYNOTE-189: pembrolizumab + chemotherapy was associated with a more than 50% reduction of risk of death (HR=0.49, P<0.001; 95% CI, 0.38-0.64) when compared to placebo + chemotherapy. mOS: median OS.

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Figure 2. Kaplan-Meier estimate for PFS in the KEYNOTE-189: pembrolizumab + chemotherapy was associated with a 48% reduction of risk of progression or death (HR=0.49, P<0.001; 95%CI, 0.38-0.64) when compared to placebo + chemotherapy. mPFS: median PFS.

Cross-Over Effect

Over 40% of patients (50% when excluding those still receiving treatment) allocated to the placebo-arm (N=206) crossed-over to receive Programmed Death 1 (PD-1)-directed therapy. The KEYNOTE-189 study allowed for cross-over and 67 patients made use of this option by receiving pembrolizumab after chemotherapy plus placebo. Another 18 patients received PD-1, and PD-1 ligand (PD-L1) directed therapy outside the KEYNOTE-189 protocol.

Translational Studies: PD-L1 Expression

In the KEYNOTE-189 study, the PD-L1 expression level was measured by tumour proportion score (TPS; % of tumour cells with membranous PD-L1 staining). Table 1 is an overview of the TPS score and related primary efficacy endpoint outcomes.

Response Rate

A significant difference (P<0.001) in objective response rate (ORR) by blinded, independent central radiologic review was observed between the pembrolizumab-chemotherapy group (ORR=47.6%; 95%CI, 42.6-52.5) and the placebo-chemotherapy group (ORR 18.9%; 95%CI, 13.8-25.0). The disease control rate (DCR) was 84.6% vs 70.4%, and the median duration of response (DOR) 11.2 months vs 7.8 months, both favouring the addition of pembrolizumab to chemotherapy.

Safety

Discontinuation of the study due to adverse events (AEs) was 13.8% in the pembrolizumab plus chemotherapy group and 7.9% for the placebo plus chemotherapy group. Just over 20% of participants discontinued pembrolizumab. In the placebo group 10.4% of participants discontinued the study. Death related to AEs occurred in 6.7% vs 5.9% for pembrolizumab vs placebo, respectively.

The only two AEs in ≥10% of participants which were more frequently seen in the experimental arm than the control arm were diarrhoea (30.9% vs 21.3%) and rash (20.2% vs 11.4%). Other Grade ≥3 AEs occurring in ≥10% of patients in were anaemia 16.3% vs 15.3% and neutropenia 15.8% vs 11.9%, both for pembrolizumab vs placebo, respectively).

Disclaimer

This article is not medical advice. Patients should seek personal assessment by a licenced specialist. Physicians are recommended to read the full publication(s) as cited in the article before making medical decisions. This article does not supersede nor replace the published article(s).

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